This proposal seeks to discover novel immunosuppressants that selectively regulate cytokine production by myeloid and lymphoid cells. The search will be directed by the application of Millennium Pharmaceuticals' QuickScan TM, a proprietary collection of extracts from phylogenetically diverse and productive fungi, to previously developed screens. The proposal seeks to address two key issues: the clinical need for better, more selective immunosuppressants, and the industrial need for efficient procedures that optimally access the extraordinary diversity inherent in culture collections. We have screened the 3,000 samples constituting QuickScan TM, and exciting results from this novel approach have led us to initiate chemical purification of several compounds. Aim I encompasses the complete purification of the most compelling leukocyte modulatory activities. In Aim II, the potential specificity of these compounds will be determined using selected cytokine as says and a comprehensive screen for cytokine and chemokine transcripts. Aim III involves the functional analysis of these compounds in an in vitro model of graft rejection. Our findings will permit the selection of the most promising drug candidates for Phase II evaluation of suppression of graft rejection and inflammation in vivo. This approach seems to have defined a productive and efficient procedure for the discovery of novel drug candidates. PROPOSED COMMERCIAL APPLICATION: The potential commercial application of this research is two-fold: the project aims to discover compounds that will lead to new immunosuppressant drugs; and through this discovery aims to bolster the efficacy of the QuickScan TM paradigm for accessing the natural chemical diversity present in fungi.